After a very challenging summer, I've finally turned in my written thesis, so it's official: I have my Ph.D. I'm publishing the abstract below. These findings should all be published in peer-reviewed journals in the next 6 months.
Ataxin-7 Conserved Motifs Determine the Severity of the Neurodegenerative Disorder Spinocerebellar Ataxia Type 7 in Transgenic Mice and Influence Lifespan in Yeast
Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant, progressive neurodegenerative disorder whose characteristic features are cerebellar ataxia, dysarthria, and retinal cone-rod dystrophy culminating in blindness. SCA7 is caused by an abnormally long glutamine-coding CAG repeat in the SCA7 gene, which encodes the protein Ataxin-7.
Ataxin-7 contains several conserved motifs that may influence the toxicity of the glutamine tract. Among these are three conserved regions (conserved block I – III), two caspase-7 cleavage sites, a nuclear export signal and two monopartite nuclear localization signals (NLS). Previous investigations have shown that the caspase-7 cleavage site D266 is required for the full toxicity of the Ataxin-7 protein in cell culture. We generated SCA7 transgenic mice expressing a 92 CAG version of the human SCA7 cDNA, with and without a D266N mutation. Mice carrying the D266N mutation were protected from SCA7-like neurodegeneration, behavioral signs and shortened lifespan.
To further characterize the role of conserved motifs in SCA7 pathology, we generated SCA7 transgenic mice carrying point mutations in both C-terminal NLSs (KKRK -> KAAK). Previous work has shown that nuclear localization is an important step in the pathology of CAG repeat disorders. We observed that mice lacking C-terminal NLS activity were substantially protected from degeneration of the retina and cerebellum, SCA7-like behavioral signs and shortened lifespan.
Age is the primary risk factor for neurodegenerative disease. Even in the absence of overt disease, the aging brain shows histopathological and molecular changes reminiscent of neurodegeneration. To explore the link between neurodegenerative disease and aging, we have examined the replicative lifespan of Saccharomyces cerevisiae missing the SCA7 ortholog, SGF73. This strain exhibits an unusually long lifespan, which is dependent on the function of the NAD+-dependent deacetylase SIR2. We present evidence that the extended lifespan of the SGF73 null strain is due to the influence of Sgf73 on the activity of Sir2 and the histone deubiquitinase Ubp8. Furthermore, we show that the level of ubiquitinated H2B is elevated in an SCA7 transgenic mouse line, indicating that an alteration in Ubp8 activity may play a role in SCA7 pathology and that aging and neurodegeneration may share a common mechanism.
FiveFingers in the Alpine Lakes Wilderness
I recently bought a pair of Vibram FiveFingers Sprint (pictured). They're minimal, lightweight shoes with "toes". They're designed to mimic barefoot walking as closely as possible, while protecting the feet from punctures and abrasion. The soles are thin, flexible and offer no padding whatsoever.I've always been a barefoot walker, because our feet evolved to be nude (or close to it). Besides feeling amazing, walking barefoot allows the body to express proper biomechanics. My feet have become tougher over time, but I still can't handle a rough trail barefoot.
When I first put the FiveFingers on, my initial thought was "these don't feel as much like being barefoot as I wish they did". Simply having something between your skin and the ground makes your feet much less sensitive. But I got used to them quickly, eventually using them for my parkour training.
I had a few converstions with my parkour instructor Rafe Kelley, during which I realized I had to re-teach myself how to walk and run correctly. Rafe is well-versed in natural human movement due to his background in MovNat, gymnastics, martial arts, strength training, parkour and anthropology. Modern shoes allow us to walk and run in a way that our bodies did not evolve to tolerate. The padding in shoes allows us to take large steps, in which we overshoot our center of gravity and contact the ground in a jarring manner. It also allows us to strike with our heels when we run, which is not comfortable when you're barefoot.
I took the FiveFingers on a 13-mile hike in the Alpine
Lakes wilderness with a few friends last weekend. The Pacific Northwest has to be one of the most beautiful places in the world. I was expecting to use the shoes for a few miles and then swap them for my lightweight hiking shoes (Inov8 Flyroc trail runners). The beginning of the trail was really rocky and I thought I was going to have to take them off in the first few hundred yards. Surprisingly, my feet adapted, and although the trail stayed rocky, it became fairly comfortable by the time we had walked a mile.I found myself thinking about Rafe's advice, and taking smaller steps that strike closer to my center of gravity. Although my strides were shorter, I had no trouble keeping up, and in fact going up the hills was remarkably easy. We gained 3,000 feet of elevation but I never got winded. I had to pay close attention to foot placement, which kept me from looking around much but was actually kind of fun.
After a few miles, I switched to my hiking shoes, with the idea that I should switch before my feet really started to hurt, rather than after. I immediately noticed that going up hills was harder, especially on my calves. My feet felt more cumbe
rsome as well.Here's me foraging for mushrooms on the trail. This is Laetiporus sulphureus, also known as "chicken of the woods". It's widely eaten in this area. However, my mushroom guide All That the Rain Primises, and More, had this to say about it:
"If you eat and enjoy this moushroom, always cook it thoroughly and do not serve it to lawyers, landlords, employers, policemen, pit bull owners, or others whose good will you cherish!"
I didn't take my chances. If you're going to pick wild mushrooms, make sure you know what you're doing and carry a regional identification guide. "I recognize them from China/Russia/Europe" kills several people a year in the Pacific Northwest. If you're experienced, this area is a mushroom bonanza. I can't set foot outside without stepping on a king bolete (porcini, cep) in the fall.
I ended up switching back to the FiveFingers for the majority of the hike, about 9 miles of it. The soles of my feet were a bit sore by the end (due to stepping on sharp rocks for miles), but my joints and muscles felt remarkably good! I had no joint pain or muscle tightness. I also felt pretty energetic. This was a big surprise, since I haven't done much hiking this year. The next day, my calves were sore, but that was it.
All in all, I really like the FiveFingers. I can wear them in places that require shoes, yet remain nearly barefoot. One potential drawback is the price-to-durability ratio. They cost me $80 and I don't expect them to last a year. That being said, I'm putting a brutal beating on them. Parkour training destroys shoes. The rubber seems to be excellent quality (which you'd expect from Vibram), but it's thin and it has cuts in it for flexibility and grip, which will lower its lifespan. The upper is simply a piece of stretchy fabric that tears easily. I'm willing to deal with the durability issues because the advantages outweigh them [update- several FiveFingers wearers have commented that they actually last a surprisingly long time. See comments].
Ischemic Heart Attacks: Disease of Civilization
Or, more precisely, disease of Western industrial civilization.
The scientific literature contains examples of cultures that don't suffer from the chronic non-communicable diseases that are so common in modern societies. Much of what I've read indicates that heart attacks are practically unique to cultures that have adopted industrial foodways and a modern lifestyle, being infrequent or entirely absent in those that have not.
I recently came across an incredible paper from 1964 in the American Journal of Cardiology, titled "Geographic Pathology of Myocardial Infarction", by lead author Dr. Kyu Taik Lee (Am. J. Cardiol. 13:30. 1964). This was published during a period of intense research into the cardiovascular health of non-industrial cultures, including Dr. George V. Mann's famous study of the Masai.
The first thing Lee and his colleagues did was collect autopsy statistics from San Francisco and Los Angeles hospitals. They analyzed the data by race, including categories for Caucasian-Americans (white), Japanese-Americans, Chinese-Americans, and Filipino-Americans. All races had a similar incidence of autopsy-proven myocardial infarction (MI = heart attack), including both silent (healed) and fatal MI. For comparison, they included a table with autopsy data from hospitals in Tokyo, South Japan and North Japan. I'm including the data from Tokyo in the graph because it's also an urban environment, but the finding was the same in all three regions. Here's what they found, by age group:
The Japanese had a very low rate of MI compared to both Caucasian-Americans and Japanese-Americans. The rate of MI in Caucasian-Americans and Japanese-Americans did not differ significantly. Thus, location but not race determined the susceptibility to MI.
Next, the investigators collected autopsy data from hospitals in New Orleans, again divided by race. This time they exained Caucasian-Americans and African-Americans. Both groups had a very high rate of MI, as expected, although the African-Americans had a lower rate than Caucasian-Americans. They also collected data from autopsies in Nigeria and Uganda for comparison. Here are the data for men:
And for women: 
Again, location but not race largely determined the incidence of MI. MI was extremely rare in the African autopsies. Here's what they had to say:
To satisfy the skeptics, Lee and colleagues imported hundreds of hearts from consecutive autopsies in Albany (USA), Africa, Korea and Japan. They had an American pathologist analyze them side-by side to eliminate any diagnostic bias. Here's what they found:
What do the traditional diets and lifestyles of Japan and Africa have in common? Not much. Even within Nigeria, the diet varies from heavily starch-based (root vegetables, soaked/fermented non-gluten grains, beans, plantains) to mostly reliant on high-fat dairy and meat. In fact, I believe it's the wrong question to ask. A better question is "what do we eat/do in the US that traditional Japanese, Koreans, Chinese, Polynesians, Melanesians and Africans don't"? For starters, none of them rely on industrial vegetable oils, sugar and wheat to nearly the same extent as modern America. Their food is generally prepared at home using wholesome ingredients and traditional methods.
They probably get more exercise than Americans, even if it's only walking in Tokyo or domestic tasks for women in parts of Africa. Traditional Africans surely get more sunlight and thus more vitamin D. I can't imagine life is less stressful in Tokyo than in San Francisco or Los Angeles.
I really like this study, and I think these graphs should be disseminated as much as possible. I've prepared high-resolution versions in JPEG, Powerpoint and PDF formats. E-mail me (click on my profile for the link) if you would like a copy. Let me know which format(s) you want.
The scientific literature contains examples of cultures that don't suffer from the chronic non-communicable diseases that are so common in modern societies. Much of what I've read indicates that heart attacks are practically unique to cultures that have adopted industrial foodways and a modern lifestyle, being infrequent or entirely absent in those that have not.
I recently came across an incredible paper from 1964 in the American Journal of Cardiology, titled "Geographic Pathology of Myocardial Infarction", by lead author Dr. Kyu Taik Lee (Am. J. Cardiol. 13:30. 1964). This was published during a period of intense research into the cardiovascular health of non-industrial cultures, including Dr. George V. Mann's famous study of the Masai.
The first thing Lee and his colleagues did was collect autopsy statistics from San Francisco and Los Angeles hospitals. They analyzed the data by race, including categories for Caucasian-Americans (white), Japanese-Americans, Chinese-Americans, and Filipino-Americans. All races had a similar incidence of autopsy-proven myocardial infarction (MI = heart attack), including both silent (healed) and fatal MI. For comparison, they included a table with autopsy data from hospitals in Tokyo, South Japan and North Japan. I'm including the data from Tokyo in the graph because it's also an urban environment, but the finding was the same in all three regions. Here's what they found, by age group:
The Japanese had a very low rate of MI compared to both Caucasian-Americans and Japanese-Americans. The rate of MI in Caucasian-Americans and Japanese-Americans did not differ significantly. Thus, location but not race determined the susceptibility to MI. Next, the investigators collected autopsy data from hospitals in New Orleans, again divided by race. This time they exained Caucasian-Americans and African-Americans. Both groups had a very high rate of MI, as expected, although the African-Americans had a lower rate than Caucasian-Americans. They also collected data from autopsies in Nigeria and Uganda for comparison. Here are the data for men:
And for women: 
Again, location but not race largely determined the incidence of MI. MI was extremely rare in the African autopsies. Here's what they had to say: There was only 1 case of healed myocardial infarction among over 4,000 adult autopsies in the Uganda series, and only 2 cases of healed myocardial infarction among over 500 adult autopsies in the Nigerian series. In the New Orleans Negro series the occurrence rate was far greater in every sex and age group than in either one of the Negro series in East and West Africa.Over 4,500 autopsies and not a single fatal MI. If this isn't worth studying, what is? These data should be part of first-year training in medicine and health programs.
To satisfy the skeptics, Lee and colleagues imported hundreds of hearts from consecutive autopsies in Albany (USA), Africa, Korea and Japan. They had an American pathologist analyze them side-by side to eliminate any diagnostic bias. Here's what they found:
In the African Negro series no infarct was found in any age group [out of 244 hearts, 39 over 60 years old]. In the Korean series there were only 2 cases of myocardial infarction [out of 106 hearts] and they were both women... In the Japanese series there were 8 cases of myocardial infarction in 259 hearts. All were men...In the American sample, nearly 40% of the hearts of men and women over 60 showed signs of MI. The findings of the American pathologist confirmed the international autopsy data, showing that diagnostic bias did not contribute to the results significantly. They also took measurements of the thickness of the coronary artery wall, an index of atherosclerosis. They found that the Americans had the most atherosclerosis, but all cultures had some degree of it and there was overlap in the amount of atherosclerosis between samples. This led the investigators to state:
Myocardial infarction and coronary thrombosis are almost nonexistent in Uganda and Nigeria, and the amount of coronary arteriosclerosis is significantly less in Africans than in whites. However, in the two groups there was some overlapping in the degree of arteriosclerosis. No Africans had infarcts, but some had the same or a greater degree of coronary arteriosclerosis as a few whites who had myocardial infarctions. One explanation for this may be that some difference in clotting or clot-lysis mechanisms is present in the two groups. In a previous study, we showed that the incidence of thromboembolic phenomena in the pulmonary circulation [blood clots in the lungs] was low in East Africans as compared with Americans.Now, the authors' conclusions:
These data strongly suggest that among the Orientals the environmental factor is playing a major role in the etiology of myocardial infarction and coronary thrombosis. If the genetic factor is an important one, those Orientals who moved to this country many years ago or who were born in this country should still maintain their low occurrence rate of myocardial infarction at least to some extent, and one would not expect to see similar occurrence rates of myocardial infarction in Orientals and whites as old as 50 to 59 years... As with the Orientals, this suggests that for Negroes in the United States environmental factors are more important than genetic factors in the etiology of myocardial infarction.Africans in Africa and Japanese in Japan = low incidence of MI. Africans, Japanese and Caucasians in the US = high and similar incidence of MI. Genes only influence a person's susceptibility to MI when they live in an environment that promotes MI. Otherwise, genes are basically irrelevant.
What do the traditional diets and lifestyles of Japan and Africa have in common? Not much. Even within Nigeria, the diet varies from heavily starch-based (root vegetables, soaked/fermented non-gluten grains, beans, plantains) to mostly reliant on high-fat dairy and meat. In fact, I believe it's the wrong question to ask. A better question is "what do we eat/do in the US that traditional Japanese, Koreans, Chinese, Polynesians, Melanesians and Africans don't"? For starters, none of them rely on industrial vegetable oils, sugar and wheat to nearly the same extent as modern America. Their food is generally prepared at home using wholesome ingredients and traditional methods.
They probably get more exercise than Americans, even if it's only walking in Tokyo or domestic tasks for women in parts of Africa. Traditional Africans surely get more sunlight and thus more vitamin D. I can't imagine life is less stressful in Tokyo than in San Francisco or Los Angeles.
I really like this study, and I think these graphs should be disseminated as much as possible. I've prepared high-resolution versions in JPEG, Powerpoint and PDF formats. E-mail me (click on my profile for the link) if you would like a copy. Let me know which format(s) you want.
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